Breast Cancer: Innovation and

Interdisciplinary CareMaen J. Farha- MUMH Breast CenterMedical Director

Objectives

• Understand the work up of a new breast abnormality• Understanding the principles of staging and

treatment• An overview of innovation• Understanding surgical treatment of breast cancer

Hypotheses of breast cancer

William Stewart Halsted, M.D. (September 23, 1852 –September 7, 1922)_ HopkinsConcentric circles of spread

• By Bernard Fisher: Chairman (1967-1994)and Scientific Director- U PittsburghSystemic disease at outset

• Current thinking:Multiple distinct diseases

Breast Cancer is Multiple Diseases

2012 Stage IV ER pos/Her2 neg: Hormonal Rx 2015 same Rx

Stage IIIA Er 60%, PR 40%, Her2 1+. Feb 2015 started preoperative

chemotherapy

7

JM Locally Advanced Breast Cancer

• Preop chemotherapy tolerated: 2/2015• Response borderline• PET/CT: Significant response to Rx: 4/2015• Radical mastectomy: 7/2015

8

JM Post Chemo and Mastectomy Pathology

• 3.6 CM IDC• 3 Positive LNs• Margins widely negative.• Swelling increases 6 weeks after surgery• Evaluation and biopsy: Metaplastic Carcinoma

9

JM October 2015, Expired 12/2015

Prior to treatment 3 months following preoperative chemotherapy, radical resection with negative margins

Staging and Other Disease Characteristics: Evaluating

the Severity of Breast Cancer

Staging

• Staging Types• TNM Staging• Stage 0• Stage 1• Stage 2• Stage 3• Stage 4

Genotypes and Phenotypes

• Estrogen/Progesterone• Her 2 receptor• Ki 67• Tumor profiling• Intrinsic subtypes

12

Oncotype DX® Recurrence Score

Calculated from 21 Different Genes

16 CANCER RELATED GENES

Paik et al. N Engl J Med. 2004;351:2817-2826.

ER

PR

Bcl2

SCUBE2

GRB7

HER2

Ki-67

STK15

Survivin

Cyclin B1

MYBL2

Stromelysin 3

Cathepsin L2GSTM1

CD68

BAG1

Beta-actin GAPDH RPLPO GUS TFRC

5 REFERENCE GENES

Estrogen Proliferation HER2 Invasion Others

NSABP B-20 Results: Tam vs. Tam + Chemo

13

28% absolute benefit from tam + chemo

INT RS

High RS

LOW RS

Paik et al. J Clin Oncol. 2006.

HER2 The Target: HER Family of

Receptors

Tyrosinekinase

domain

Ligand-bindingdomain

Heregulin

NRG2

NRG3

Heregulins

Betacellulin

Transmembrane

HER1erb-b1EGFR

HER2erb-b2neu

HER3 erb-b3

HER4erb-b4

EGF

TGF

Amphiregulin

Betacellulin

HB-EGF

Epiregulin

Ligands

HER = human epidermal growth factor receptor; EGF=epidermal growth factor, TGF=transforming growth factor, HB-EGF=heparin binding EGF

Yarden Y & Sliwkowski MX. Nature Reviews, 2001; 2:127-137.

HER2 The Therapeutic Target: Trastuzumab

Mechanism of Action (MOA)• Humanized monoclonal

antibody specific for HER2

• Targets HER2 protein-overexpressing cells

• Proposed mechanism of action based on preclinical studies– Extracellular– Intracellular

Arnould, et al. 2006. Bianco, 2004. Harari and Yarden, 2004. Lewis, et al. 1993. Sliwkowski, et al. 1999. Yakes, et al. 2002. Yarden, 2001.

Herceptin® (trastuzumab) [prescribing information]. South San Francisco, CA: Genentech, Inc.; 2010.

DimerizedHER2

receptors signal tumor

cells to proliferate

Extracellular

Trastuzumab binds to

subdomain IV of HER2 receptors

on tumor cells, flagging them for

destruction by the immune

system

Intracellular

Trastuzumab blocks HER2 signaling to

inhibit proliferation of

turmor cells

Early Detection and Screening

• Screening Mammography• Screening MRI• Screening Ultrasound

16

Diagnostic Studies

• Screening Mammogram• Diagnostic mammogram• Ultrasound• Breast MRI• PEM/ Nuclear imaging

• BIRADS:0- Needs additional imaging1- Negative2- Benign finding3- Probably benign4- Suspicious5- Highly suspicious6- Known cancer

Mammography

Biopsy intruments

Principles of treatment: Individualized

Treatment Plans• Local-Regional: Breast

and axillae• Systemic or the potential

for systemic disease• The person: Physical and

emotional well-being

Treatment Principles

• Stage 0,1 and 2: A large majority are amenable to lumpectomy and radiation therapy

• Stage 3 and many stage 2 patients may benefit from preop chemotherapy

• Stage IV treatment is palliative: Prolong life, control or prevent symptoms and improve the quality of life

Lumpectomy, SLN biopsy and Radiation

Therapy• Most common breast surgery operation• Designing our surgery reduces reoperation rate• Post lumpectomy radiation:

Standard WBI: 5-6 weeksHyperfractionation: 3 week Canadian fractionationAPBI: 5 days, 2x daily 1-3 weeks postopIORT: 10 minutes during surgery

LB ER/PR Pos Local Disease

Lessons learned from application of IORT (Intra-

Operative Radiation Therapy) as a treatment modality for

DCIS and early stage breast cancer

Introduction

Partial breast radiation has replaced whole breast radiation for many patients with early breast cancer. Intra-operative radiation therapy(IORT) is one form of partial breast radiation that offers selected patients great convenience. One of its theoretical benefits is being able to deliver the radiation specifically to the bed of the resected tumor. We have set out to review our initial experience and extracting lessons from the first 30 consecutive intraoperative radiation therapy cases using the XOFT eBX system after lumpectomy for DCIS and early stage breast. The radiation source used in Xoft eBXis a miniaturized 50 kV X-ray tube located at the tip of the source delivers a brachytherapy radiation through applicator. The dosimetry characteristic of the source is similar to Iridium-192 dosimetry and it has been designed to deliver a high dose rate of radiation into the tissue surrounding the applicator that has been inserted into the treatment cavity.

cancer. IORT was successfully completed in all of first 30 patients.We reviewed indications, complications, technical factors and outcomes.We are developing a

tool to classify patients who are being considered for IORT into the various favorable or unfavorable categories according to currently published partial breast radiation guidelines.

Methods

Our breast service initiated an intra-operative electronic brachytherapy(IORT) program in October 2013. We have maintained a prospective database of all our patients and are reporting on the first 30 consecutive cases that were offered and treated with IORT at the time of their lumpectomy. The information was recorded prospectively or obtained from the patients' medical record. Institutional IRB approval was obtained for this study.

Our patients were discussed in our multidisciplinary tumor board and then evaluated concomitantly by breast surgery, medical and radiation oncology.

Patients were selected that:1- Have favorable disease that is suitable for accelerated partial breast radiation(APBI) by

ASTRO or ASBS guidelines2- Patients who would not be able to perform whole breast radiation or3- When compliance with treatment is highly questionable

Surgical planning and needle localization plans were developed in collaboration with our breast imaging team. The ultrasound was used intraoperatively to:

1- Design our incision and the lumpectomy taking into consideration tumor location and its distance from the skin and the chest wall.

2- Evaluate margins when a tumor is visible by ultrasound and3- Radiation balloon to skin distance and cavity conformation with the radiation balloon

All lumpectomy specimen were sent for gross evaluation in pathology. Additional margins were obtained if needed prior to balloon placement.

Results

IORT was offered and completed successfully for the 30 consecutive patients with an age range of 56-96.

Stage distribution and tumor size: Stage 0: 8/30, Stage I 15/30, Stage II 6/30, Stage III 1/30.Tumor size ranged from no residual in 1 patient to 37 mm. All margins were negative except one

patient with focal DCIS involvement. The patient is elderly and was offered hormonal therapy only.

Additional radiation:Three patients needed whole breast radiation without a boost to the tumor bed.Two of these 3 patients had ER positive, Her2 negative sub-centimeter primaries with a positive

lymph node. One patient was found to have 9 positive lymph nodes despite a negative axillary ultrasound. That is the same patient who had a 37 mm ILC who was offered the treatment because of serious concern about the patient's compliance with whole breast radiation.

Receptor Status:Two patients were triple negative and one patient was triple positive; all received chemotherapy.

The remaining patients were hormone positive and Her2 negative.

Skin Spacing:It is required to have at least 10 mm distance between the brachytherapy balloon to the skin in

order to deliver the radiation safely. Skin spacing in our patients was 9.8-20.9 mm.We injected saline to increase the balloon to skin distance in the 1 patient with 9.8mm skin distance.

Balloon Size and seroma formation:Twenty one of 30 patients required a 3-4 cm spherical balloon. 4-5 cm spherical balloons were

used in the rest. We experienced three seromas with one suspected infection early in this experience . That problem was eliminated with the use of JP drains based on the surgeon's clinical judgement.

Follow up:We have not experienced any local recurrences thus far with a median follow up of 1 year

Conclusions

1- IORT can be safely and successfully implemented with low complication and re-operation rates. The successful implementation of such a program depends on patient selection, collaboration with other specialties, designing surgery utilizing intra-operative ultrasound and skin excision when tumor proximity to the skin is noted on imaging.

2- Intra-operative ultrasound use and gross pathology consultation may decrease re-operative rates.

3- Selective drains should be considered to reduce seromaformation.

Maen J. Farha, FACS Patrick E. Assi, MD Paul B. Fowler, MD

Department of Surgery, Medstar Union Memorial Hospital, Baltimore, Maryland, USA

Indidualized Rx: Bilateral Favorable Breast Cancers

2006

Individualized Rx: Locally Advanced

Locally Advanced

Locally Advanced Triple Negative Cancer JT

Triple Negative After 3 Cycles of

ChemotherapyCompletion of chemotherapy Post resection

Individualized Rx: Massive Sarcoma in a 55 Y/O School

Teacher

Individualized Rx: Massive Sarcoma in a 55 Y/O School

Teacher

Resection with LD flap Post Surgery

• Chemotherapy• Chest wall radiation

Alive and well 5.5 years later

Individualized Rx: Local Recurrence 15 Years

Later

NSM with immediate reconstruction

Hallmarks of Our Program: Multidisciplinary

Clinic and Care• Multi D clinic started 2 years ago• MultiD conference: Surgery, medical and radiation

oncology, radiology, pathology, social work, genetic counselor, rehab….

• Patients evaluated and individual plan developed• Survivorship

Teamwork• Multi D conference • Dedicated Team

Conclusions

• Lumpectomy and XRT have largely replaced mastectomy• IORT may replace over 1/3 of WBI cases• The multi disciplinary approach and adjuvant therapies have extended

patient survival• Breast cancer is a host of different syndromes which will be treated

differently in the future• Radical surgical procedures are still indicated in some patients

37